Alcohol and Impairment of the Granulopoietic Response to Pneumonia

描述（由申请人提供）：肺炎是美国感染性死亡的主要原因。酒精使宿主容易受到细菌感染，尤其是肺炎。酒精滥用肺炎患者经常出现粒细胞减少症，这是死亡率增加的一个指标。酒精损伤肺部感染骨髓粒细胞生成反应的机制尚不清楚。在肺部感染期间，受感染组织产生的粒细胞集落刺激因子（G-CSF）显著增加。G-CSF是一种必需的粒细胞生成细胞因子，可刺激骨髓中骨髓祖细胞增殖和粒细胞生成。G-CSF与其受体结合激活p44/42-cyclin D通路，促进髓祖细胞增殖。G-CSF还激活转录3 (STAT3)-周期蛋白依赖性激酶（CDK）抑制剂p27Kip1通路的信号换能器和激活器，提供负反馈信号导致G1细胞周期阻滞。我们的初步数据显示，酒精可抑制肺炎球菌肺炎或G-CSF刺激下的粒细胞祖细胞增殖。酒精抑制g - csf诱导的p44/42-cyclin D通路的激活，同时增强STAT3- p27Kip1负信号通路。在这个项目中，我们将研究酒精损害细菌性肺炎的粒细胞生成反应的细胞信号机制。我们的假设是，酒精通过损害髓系祖细胞中的G-CSF信号传导抑制对肺炎球菌肺炎的粒细胞生成反应。提出了两个具体目的：1)通过抑制g - csf诱导的颗粒生成细胞p44/42-cyclin D通路的激活，验证酒精抑制颗粒生成细胞对肺部感染反应的假设；2)通过增强STAT3-p27Kip1负反馈通路，验证酒精在G-CSF作用下损害髓系祖细胞增殖的假说。还将研究酒精代谢产生的氧化应激对G-CSF信号两个分支的直接影响和间接影响。本研究将为重度感染的酗酒者粒细胞减少的发病机制提供新的信息。它还可以确定有效治疗这些免疫功能低下患者肺炎的潜在治疗方法。

DESCRIPTION (provided by applicant): Pneumonia is a leading cause of infectious death in the United States. Alcohol predisposes the host to bacterial infections, particularly pneumonia. Alcohol abusing patients with pneumonia frequently present with granulocytopenia, which is an indicator of increased mortality. The mechanisms by which alcohol injures the marrow granulopoietic response to lung infection remain unclear. During pulmonary infection, the production of granulocyte colony-stimulating factor (G-CSF) by infected tissue is significantly increased. G-CSF is an essential granulopoietic cytokine that stimulates myeloid progenitor cell proliferation and granulocyte production in bone marrow. Binding of G-CSF to its receptor activates the p44/42-cyclin D pathway to promote myeloid progenitor cell proliferation. G-CSF also activates signal transducer and activator of transcription 3 (STAT3)-cyclin-dependent kinase (CDK) inhibitor p27Kip1 pathway that provides a negative feedback signal to cause G1 cell cycle arrest. Our preliminary data show that alcohol suppresses granulopoietic progenitor cell proliferation in response to pneumococcal pneumonia or G-CSF stimulation. Alcohol inhibits G-CSF-induced activation of the p44/42-cyclin D pathway while it enhances STAT3- p27Kip1 negative signaling. In this project, we will investigate the cell signaling mechanisms by which alcohol impairs the granulopoietic response to bacterial pneumonia. Our hypothesis is that alcohol suppresses the granulopoietic response to pneumococcal pneumonia by impairing G-CSF signaling in myeloid progenitor cells. The proposed two specific aims are: 1) To test the hypothesis that alcohol inhibits the granulopoietic response to lung infection by inhibiting G-CSF-induced activation of the p44/42-cyclin D pathway in granulopoietic cells; 2) To test the hypothesis that alcohol impairs myeloid progenitor cell proliferation in response to G-CSF by enhancing the STAT3-p27Kip1 negative feedback pathway. The direct effects of alcohol versus indirect effects of oxidative stress generated from alcohol metabolism on both branches of G-CSF signaling will also be studied. This investigation will provide novel information focused on the pathogenesis of granulocytopenia in alcohol abusers with serious infections. It may also identify potential therapeutic approaches for the effective treatment of pneumonia in these immunocompromised patients.